Reactivation of latent varicella zoster virus (VZV) leads to herpes zoster (HZ, also known as shingles), a disease that causes major morbidity and occasionally mortality in older individuals. The incidence of HZ increases from 3.3 per 1000 person-years at age 40-49 to 7.7 at age 60-69. Advanced age is the primary risk factor not only for developing HZ, but also complications such as post herpetic neuralgia, vasculopathies and zoster opthalmicus. Current estimates predict that by 2020 more than 70 million Americans will be over the age of 65 therefore, the incidence of HZ and associated complications will certainly increase. Furthermore, the currently approved vaccine against HZ reduces the incidence of shingles by only 51%. Thus, a significant portion of the vaccine recipients still remains susceptible to VZV reactivation. A major obstacle in developing better treatments and vaccines for HZ is that models utilizing VZV infection of laboratory animals do not produce signs of in clinical disease that occur in humans. Consequently, our understanding of the immune correlates of protection against VZV infection and reactivation remains very limited due to lack of a suitable animal model to study host-pathogen interactions in vivo. We have developed a nonhuman primate model wherein young rhesus macaques infected with a primate homologue of human VZV, simian varicella virus (SVV) display the hallmarks of VZV infection in humans; i.e., the appearance of generalized varicella rash, the development of cellular and humeral immunity, and the establishment of latency with limited transcriptional activity in sensory ganglia. In contrast to young rhesus macaques, aged animals infected with SVV remain persistently viremic. In aged monkeys, persistent lytic replication occurred despite the development of an IgG antibody response that was comparable to that generated by young animals. On the other hand, SVV-specific T cell responses in aged animals were significantly delayed compared to those generated by young animals. These data strongly suggest that, as described for VZV, defects in T cell responses in aged animals result in poor immunological control of SVV replication and dissemination. Further evidence for this hypothesis was obtained from young rhesus macaques depleted of either CD4 or CD8 T cells and then infected with SVV. In CD8 T cell-depleted animals, SVV antigen was persistently detected in the lungs despite presence of a comparable IgG response to non-depleted controls. In CD4 T cell-depleted animals, the IgG response was significantly delayed and reduced. However, although IgG titers reached comparable levels as the controls in one CD4 T cell-depleted animal, it remained persistently viremic nevertheless. These data strongly suggest that, as described for VZV, the development and maintenance of a robust T cell response is critical to the control of SVV infection. Therefore, SVV infection of young and aged rhesus macaques provides a unique opportunity to: (1) identify age-related differences in the SVV-specific T cell responses and (2) determine how these differences in immune responses affect the aged animal's ability to control SVV replication and to maintain latency. These studies will improve our understanding of immunological control of latent VZV as well as other latent pathogens that pose significant health issues for the elderly.